Hypoxia refers to a pathological process in which the metabolism, function and morphological structure of the tissue are abnormally changed due to lack of oxygen supply or oxygen impairment. Such pathologies as shock, respiratory dysfunction, cardiac insufficiency and anemia, etc. could impair organs vital to life like brain and heart and even cause people to die. Hypoxia is also common in environmentally-affected pathological process. High-altitude flight, diving and work in severe hypoxic environment such as plateau, air-tight cabin or tunnels will directly influence human activities and even threat their lives. Therefore, it is of great social significance to study and develop antihypoxic drugs.
Hypoxia could slow down the aerobic metabolism of the tissues all over the body. It is indicated by many researches that mitochondria damage may be the core of energy metabolism dysfunction for cell after hypoxia. In the circumstance of hypoxia, large numbers of free radicals are produced by the organism. Mitochondria, the main producer for endogenous free radical, are the target of free radicals. Oxygen free radicals produced after hypoxia can make toxic reaction to biomacromolecule, mainly reflecting in lipid peroxidation, which can cause abnormal membrane structure and dysfunction. The fluidity of mitochondria decreases after they are impaired by free radicals, thus decreasing the function of the mitochondria and slowing down the activity of the enzyme in the membrane. The degradation of mitochondrial membrane phospholipids can lead to damage to mitochondria, which will influence the activity of cytochrome c-oxidase and ATP synthase, decreasing the synthesis of ATP and directly cause cell impairment of the organism and energy metabolism impairment. Therefore, the most important prophylaxis and treatment for hypoxia is to guarantee oxygen supply to the organism so as to maintain healthy working of its energy metabolism, prevent and treat impairment of the histocyte. Clinically, dizziness, encephalalgia, tinnitus, dim sight, limb asthenia, decreasing exercise capacity, mental slowness and memory deterioration, or nausea, emesis, palpitation, brachypnea, polypnea and rapid and weak heart beat are general illnesses of hypoxia. In addition, hypoxia can also cause severe complications including, among others, myocardial infarction, angina pectoris, heart failure, pulmonary edema and cerebral edema, respiratory disorder, injury of optic nerve, injury of cranial nerve and cerebral apoplexy.
Hypoxia can be classified into four types: hypotonic hypoxia, anemic hypoxia, circulatory hypoxia and histogenous hypoxia. Anemic hypoxia and histogenous hypoxia are caused by oxygen impairment, while hypotonic hypoxia and circulatory hypoxia are caused by lack of oxygen supply. Clinically, the co-existence of mixed hypoxia, hypotonic hypoxia and circulatory hypoxia is common.
Hypotonic hypoxia, a common hypoxia in industrial production and daily life, refers to hypoxia caused by lack of oxygen supply to the organism due to obvious decrease of oxygen partial pressure, such as hypoxia caused by external respiratory dysfunction, high altitude hypoxia, aerohypoxia, tunnel hypoxia, diving hypoxia and airtight cabin hypoxia, among which high altitude hypoxia is very common and is the core of hypoxia prophylaxis and treatment.
Tunnel hypoxia refers to hypoxia caused by the fact that the proportion of oxygen in bottom air in the tunnel or cave of a certain depth decreases due to the high proportion of carbon dioxide, leading to decrease of oxygen partial pressure. Diving hypoxia and airtight cabin hypoxia refer to hypoxia caused by the decrease of oxygen partial pressure due to the lower oxygen proportion in the environment. The most common prophylaxis to the said hypoxia is fresh air supplement, oxygen uptake and evacuation from oxygen-lacking area; however, there is not any drug means.
High altitude hypoxia and aerohypoxia refer to hypoxia which occurs, in plateau or high altitude area with an altitude of over 3000 meters, due to low air pressure and accordingly decreased oxygen partial pressure, and reduced difference of oxygen partial pressure in the atmosphere and alveoli with the increase of altitude, directly influencing alveolar gas exchange, oxygen carrying capacity of the blood and release speed of the binding oxygen in the organism, and further leading to lack of oxygen supply to the organism. Acute high altitude stress occurs when people live in the plain go to the plateau of above 3000 m within a short time, or when people live in the plateau go to the plain and then return to the plateau after a period of time. The mild one has the illnesses of encephalalgia, dizziness, palpitation and brachypnea, while the severe one has the illnesses of loss of appetite, nausea, emesis, insomnia, fatigue, hypouresis, abdominal distension and chest distress. Clinically, cyanosis of lips and face, hand and ankle edema are common More severe acute high altitude stress can lead to vasoconstriction of the small pulmonary vein and increase resistance, and then cause pulmonary hypertension and the increase of pulmonary capillary permeability. In addition, hypoxia can also cause lymphatic circulatory disturbance. Therefore, pulmonary edema occurs, and may lead to spasm of small brain vascular and increase the permeability and further cause other acute high altitude stress like brain edema. High altitude stress will be developed into chronic high altitude stress once it lasts for three months. If the symptom of high altitude hypoxia cannot disappear automatically, it will cause people to die due to the necrosis of such vital organs as heart, brain and lung. Traditional non-drug treatments for high altitude hypoxia are high pressure oxygen uptake and evacuation from high altitude area. It is of good efficiency, but cannot be used widely subject to conditions. Adjuvant treatment of drugs is often used for high altitude hypoxia. Clinically, diuretics acetazolamide, corticoid dexamethasone, vasodilator nimodipine, vitamins and aminophylline are used, but their effect is limited. Acetazolamide is most commonly used, but it only works to a certain degree for people who stay in the plateau area for short time. For people who stay in the plateau area for long time, it cannot be taken for a long period since it can easily cause such adverse reactions as electrolyte disturbance, polyuria and dehydration. Other drugs such as hormone also cannot be taken for a long period. In addition, rhodiola-contained traditional Chinese medicine preparation which can assist in enhancing the adaptability to hypoxia is also used for hypoxia prophylaxis and treatment. But it works slowly with a limited effect for anti-hypoxia. According to literature (Chinese Invention Patent, Application No. 200310104871.X), supplement of L-carnitine can prevent and treat high altitude stress. Survival time test of anoxic mice under normal pressure and swimming test of mice under low pressure prove that L-carnitine works to some degree for anti-hypoxia under low pressure. L-carnitine can promote the fatty acid metabolism, reduce the accumulation of acid metabolites such as lactic acid and increase energy supply, reduce the content of free fatty acid and acyl fatty acid by promoting fatty acid oxidation, and reduce the damage to cell membrane, increase the stability of cell membrane, especially vital tissue cells like myocardial cells and brain cells and to a certain degree play a role in anti-hypoxia. But fatty acid oxidation needs to consume large amounts of oxygen, so oxygen supply is limited under the circumstance of hypoxia. Therefore, L-carnitine may aggravate hypoxia due to large amounts of oxygen consumption when promoting fatty acid oxidation.
Circulatory hypoxia is also common in clinical practice. Circulatory hypoxia, also known as hypokinetic hypoxia, refers to hypoxia caused by reduced oxygen supply to the tissue due to decreased blood flow. It mainly occurs to patients with heart disease, angina pectoris, cardiac insufficiency, myocardial infarction, heart failure, diseases caused by blood vessel blockage, cerebral apoplexy and arteriovenous atherosclerosis. In clinic practice, drugs such as nitrate, β adrenoceptor antagonist and Ca-antagonist which can change hemodynamics and cerebral vasodilator vinpocetine are often used. The role of the above-mentioned drugs in prophylaxis and treatment of tissue cell impairment of the organism caused by hypoxia is limited and cannot meet the need to prevent and treat circulatory hypoxia. Moreover, trimetazidine which does not change hemodynamics is also used in clinic practice to treat circulatory hypoxia of heart and brain. Trimetazidine, a strong anti-angina drug, is often used in clinic practice to treat coronary insufficiency, stenocardia and previous myocardial infarction. It works slower than nitroglycerin, but its effect can last for longer time. 60%-70% normal myocardial energy (ATP) supply comes from the oxidation of free fatty acid β, 20%-25% the oxidation of glucose, and 5%-10% the glycolysis. Trimetazidine can inhibit fatty acid oxidation, promote glucose oxidation, and work to some degree for anti-myocardial ischemia, but glucose oxidation can only provide 20% energy, far from enough to meet the energy needed to the activities of heart and skeletal muscle. Trimetazidine's inhibition of fatty acid oxidation could cause the accumulation of large numbers of fatty acids, which will damage cell membrane and mitochondria structure, reduce the activity of pyruvate dehydrogenase, and in return inhibit glucose oxidation. Therefore, there are some shortcomings using trimetazidine alone for prophylaxis and treatment of hypoxia.
In conclusion, there is still a gap in developing an ideal antihypoxic drug, which shall first guarantee under the condition of low pressure or low oxygen (hypotonic hypoxia or circulatory hypoxia) the oxygen supply to the organism and its normal energy metabolism, protect impaired tissue cells due to hypoxia, and have no obvious adverse effect for long-term taking. It shall have the features of prophylaxis and treatment. Obviously, there is a lack of such pharmaceutical preparation with the said features and stable quality in the market.